Faculty Bibliography

Background Autoantibody landscapes are very specific to the individual, can remain stable for many years, and contain unique features reported in association with cancer, autoimmunity, infection, neurologic conditions, CD8+ T cell behavior, and checkpoint blockade adverse events [1-11]. The goal of this work was to determine whether pre-existing antigenspecific features in melanoma patient autoantibody landscapes would associate with clinical outcomes following checkpoint blockade. Methods Pre-treatment serum samples were collected from 117 melanoma patients prior to checkpoint blockade with anti-CTLA4 (N=60), anti-PD1 (N=38), or both in combination (N=16). All data was collected with approval of the NYU Institutional Review Board at the NYU Perlmutter Cancer Center with informed consent [11]. Serum samples were run on HuProt Human Proteome Microarrays containing >19,000 human proteins by CDI Laboratories. Raw serum IgG signal intensities were processed across staining cohorts via interquartile range normalization. Pre-existing antibody responses were defined as patient-specific IgG signals >3.5 median absolute deviations above cohort median IgG background (modified Z-score). Group statistics were computed (GraphPad Prism), and gene ontology enrichment analysis was performed (Enrichr) [12]. Results Several pre-existing antigen-specific IgG autoantibody targets were observed to have associations with good outcomes (SD/PR) or objective clinical responses (PR/CR) versus patients with progressive disease (POD). While final determination of the most predictive subsets is ongoing, many targets represent genes in an axis surrounding immune signaling pathways, hereditary neurodegenerative disease, and the ubiquitin proteasome pathway (ie, UBQLN1, UBQLN2). An exemplary example was observed in the autoantibody responses shared by >10% of all patients regardless of clinical outcome. Gene ontology enrichment analysis of these shared melanoma-patient autoantibodies versus KEGG 2019 [12] demonstrates this set of proteins is strongly enriched for neurotrophin signaling-associated proteins after multi-sample correction (P=0.004) (Table 1). Several other associations were observed cohort-wide for ontologies with tissuespecific enrichment in the brain, neurons, and neuronal processes. Conclusions In this pilot study, we found strong associations across the cohort for autoantibodies against nerve-growth-inducing neurotrophins and genes like UBQLN1 and UBQLN2 which have strong associations with amyotrophic lateral sclerosis, frontotemporal dementia, Parkinson's, and Alzheimer's - neurodegenerative diseases that are known to have incidences which correlate with melanoma [14-16]; this hints at a potential immunologic connection between the conditions, perhaps related to an antitumor / autoimmune axis involving the targets reported here. (Table Presented)

Background Dietary interventions may play a role in secondary cardiovascular prevention. hsCRP (High-sensitivity C-reactive protein) is a marker of risk for major adverse cardiovascular outcomes in coronary artery disease. Methods and Results The open-label, blinded end-point, EVADE CAD (Effects of a Vegan Versus the American Heart Association-Recommended Diet in Coronary Artery Disease) trial randomized participants (n=100) with coronary artery disease to 8 weeks of a vegan or American Heart Association-recommended diet with provision of groceries, tools to measure dietary intake, and dietary counseling. The primary end point was high-sensitivity C-reactive protein. A linear regression model compared end points after 8 weeks of a vegan versus American Heart Association diet and adjusted for baseline concentration of the end point. Significance levels for the primary and secondary end points were set at 0.05 and 0.0015, respectively. A vegan diet resulted in a significant 32% lower high-sensitivity C-reactive protein (β, 0.68, 95% confidence interval [0.49-0.94]; P=0.02) when compared with the American Heart Association diet. Results were consistent after adjustment for age, race, baseline waist circumference, diabetes mellitus, and prior myocardial infarction (adjusted β, 0.67 [0.47-0.94], P=0.02). The degree of reduction in body mass index and waist circumference did not significantly differ between the 2 diet groups (adjusted β, 0.99 [0.97-1.00], P=0.10; and adjusted β, 1.00 [0.98-1.01], P=0.66, respectively). There were also no significant differences in markers of glycemic control between the 2 diet groups. There was a nonsignificant 13% reduction in low-density lipoprotein cholesterol with the vegan diet when compared with the American Heart Association diet (adjusted β, 0.87 [0.78-0.97], P=0.01). There were no significant differences in other lipid parameters. Conclusions In patients with coronary artery disease on guideline-directed medical therapy, a vegan diet may be considered to lower high-sensitivity C-reactive protein as a risk marker of adverse outcomes. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 02135939.

BACKGROUND:Studies have demonstrated the value of transthoracic echocardiogram (TTE) diastolic parameters in predicting left atrial appendage (LAA) thrombus; however, these studies have been small. We aim to clarify the relationship between TTE diastolic parameters, in particular average e', and LAA thrombus or sludge. METHODS:A case-control review was conducted of subjects with non-valvular atrial fibrillation (n = 2263) who had undergone TEE (transesophageal echocardiogram) and had a TTE within 1 year of TEE. Cases of LAA sludge or thrombus were matched to controls by age, sex, left ventricular ejection fraction (LVEF), and anticoagulation status. RESULTS:Forty-three subjects (mean age 73 ± 12, 65% male, LVEF 47%, 44% on anticoagulation) with LAA sludge or thrombus were identified. Compared to matched controls, average TTE e' (7.3 ± 2.1 cm/s vs 8.7 ± 2.1 cm/s, P < 0.001) and the E:e' ratio (15 ± 7 cm/s vs 12 ± 5 cm/s; P = 0.005) were significant predictors of LAA sludge or thrombus. Average TTE e' value of >11 cm/s had 100% sensitivity for ruling out LAA sludge or thrombus. CONCLUSION/CONCLUSIONS:In individuals with atrial fibrillation, average e' >11 cm/s on TTE is a promising independent predictor of the absence of LAA sludge or thrombus on TEE.

INTRODUCTION/BACKGROUND:Blood donation has been proposed as a potential therapy to reduce risk of cardiovascular disease, but the effects of phlebotomy on vascular function in human subjects have not been well characterized. AIMS/OBJECTIVE:We conducted a prospective randomized double-blind study to determine the effects of serial phlebotomy on vascular endothelial function in the brachial artery. 84 iron-replete, non-anemic subjects were randomly assigned to one of three study treatment groups: 1) four serial phlebotomy procedures each followed by intravenous infusion of placebo normal saline; 2) four serial phlebotomy procedures each followed by intravenous infusion to replete lost iron; and 3) four serial sham phlebotomy procedures each followed by intravenous infusion of placebo normal saline. Assigned phlebotomy procedures were conducted at 56-day intervals. We measured brachial artery reactivity (BAR, %) in response to transient oxidative stress induced by oral methionine with high-resolution duplex ultrasound imaging before and one week after the fourth study phlebotomy. RESULTS:Before phlebotomy, oral methionine decreased BAR by -2.04% (95% CI -2.58, -1.50%), p<0.001) with no significant difference between groups (p=0.42). After phlebotomy, the BAR response to oral methionine did not significantly change between groups (p=0.53). Brachial artery nitroglycerin-mediated dilation did not change in response to phlebotomy. CONCLUSIONS:Four serial phlebotomy procedures over six months with or without intravenous iron supplementation did not alter vascular endothelial function in the brachial artery when compared with sham phlebotomy.

OBJECTIVES/OBJECTIVE:The aim of this study was to determine whether frailty is associated with increased bleeding risk in the setting of acute myocardial infarction (AMI). BACKGROUND:Frailty is a common syndrome in older adults. METHODS:Frailty was examined among AMI patients ≥65 years of age treated at 775 U.S. hospitals participating in the ACTION (Acute Coronary Treatment and Intervention Outcomes Network) Registry from January 2015 to December 2016. Frailty was classified on the basis of impairments in 3 domains: walking (unassisted, assisted, wheelchair/nonambulatory), cognition (normal, mildly impaired, moderately/severely impaired), and activities of daily living. Impairment in each domain was scored as 0, 1, or 2, and a summary variable consisting of 3 categories was then created: 0 (fit/well), 1 to 2 (vulnerable/mild frailty), and 3 to 6 (moderate-to-severe frailty). Multivariable logistic regression was used to examine the independent association between frailty and bleeding. RESULTS:Among 129,330 AMI patients, 16.4% had any frailty. Frail patients were older, more often female, and were less likely to undergo cardiac catheterization. Major bleeding increased across categories of frailty (fit/well 6.5%; vulnerable/mild frailty 9.4%; moderate-to-severe frailty 9.9%; p < 0.001). Among patients who underwent catheterization, both frailty categories were independently associated with bleeding risk compared with the non-frail group (vulnerable/mild frailty adjusted odds ratio [OR]: 1.33, 95% confidence interval [CI]: 1.23 to 1.44; moderate-to-severe frailty adjusted OR: 1.40, 95% CI: 1.24 to 1.58). Among patients managed conservatively, there was no association of frailty with bleeding (vulnerable/mild frailty adjusted OR: 1.01, 95% CI: 0.86 to 1.19; moderate-to-severe frailty adjusted OR: 0.96, 95% CI: 0.81 to 1.14). CONCLUSIONS:Frail patients had lower use of cardiac catheterization and higher risk of major bleeding (when catheterization was performed) than nonfrail patients, making attention to clinical strategies to avoid bleeding imperative in this population.

OBJECTIVE:To analyze trends in the incidence, in-hospital management, and outcomes of acute myocardial infarction (AMI) complicating pregnancy and the puerperium in the United States. PATIENTS AND METHODS/METHODS:Women 18 years or older hospitalized during pregnancy and the puerperium were identified from the National Inpatient Sample database from January 1, 2002, to December 31, 2014. International Classification of Diseases, Ninth Revision diagnosis and procedure codes were used to identify AMI during pregnancy-related admissions. RESULTS:Overall, 55,402,290 pregnancy-related hospitalizations were identified. A total of 4471 cases of AMI (8.1 [95% CI, 7.5-8.6] cases per 100,000 hospitalizations) occurred, with 922 AMI cases (20.6%) identified in the antepartum period, 1061 (23.7%) during labor and delivery, and 2390 (53.5%) in the postpartum period. ST-segment elevation myocardial infarction occurred in 1895 cases (42.4%), and non-ST-segment elevation myocardial infarction occurred in 2576 cases (57.6%). Among patients with pregnancy-related AMI, 2373 (53.1%) underwent invasive management and 1120 (25.1%) underwent coronary revascularization. In-hospital mortality was significantly higher in patients with AMI than in those without AMI during pregnancy (adjusted odds ratio, 39.9; 95% CI, 23.3-68.4; P<.001). The rate of AMI during pregnancy and the puerperium increased over time (adjusted odds ratio, 1.25 [for 2014 vs 2002]; 95% CI, 1.02-1.52). CONCLUSION/CONCLUSIONS:In patients hospitalized during pregnancy and the puerperium, AMI occurred in 1 of every 12,400 hospitalizations and rates of AMI increased over time. Maternal mortality rates were high. Additional research on the prevention and optimal management of AMI during pregnancy is necessary.

BACKGROUND:Elevated stress is associated with adverse cardiovascular disease outcomes and accounts in part for the poorer recovery experienced by women compared with men after myocardial infarction (MI). Psychosocial interventions improve outcomes overall but are less effective for women than for men with MI, suggesting the need for different approaches. Mindfulness-based cognitive therapy (MBCT) is an evidence-based intervention that targets key psychosocial vulnerabilities in women including rumination (i.e., repetitive negative thinking) and low social support. This article describes the rationale and design of a multicenter randomized controlled trial to test the effects of telephone-delivered MBCT (MBCT-T) in women with MI. METHODS:We plan to randomize 144 women reporting elevated perceived stress at least two months after MI to MBCT-T or enhanced usual care (EUC), which each involve eight weekly telephone sessions. Perceived stress and a set of patient-centered health outcomes and potential mediators will be assessed before and after the 8-week telephone programs and at 6-month follow-up. We will test the hypothesis that MBCT-T will be associated with greater 6-month improvements in perceived stress (primary outcome), disease-specific health status, quality of life, depression and anxiety symptoms, and actigraphy-based sleep quality (secondary outcomes) compared with EUC. Changes in mindfulness, rumination and perceived social support will be evaluated as potential mediators in exploratory analyses. CONCLUSIONS:If found to be effective, this innovative, scalable intervention may be a promising secondary prevention strategy for women with MI experiencing elevated perceived stress.

To determine whether arterial responsiveness is impaired among patients with gout, and whether arterial responsiveness inversely correlates with serum urate and inflammatory measures. This is a cross-sectional study of untreated gout subjects (n = 34) and non-gout healthy controls (n = 64). High-resolution dynamic ultrasound-measured flow-mediated dilation (FMD) and nitroglycerin-mediated dilation (NMD) assessed endothelium-dependent and endothelium-independent arterial responsiveness respectively. Serum urate (sUA) and high-sensitivity C-reactive protein (hsCRP) were measured in the gout group, and correlated with FMD and NMD responses. Both FMD (2.20 ± 0.53 vs 3.56 ± 0.31, p = 0.021) and NMD (16.69 ± 1.54 vs 24.51 ± 0.90, p = 0.00002) were impaired in the gout versus control group. Stratification for individual comorbidities suggested that no single risk factor accounted for impaired FMD/NMD in the gout subjects. However, the degree of association between gout and FMD, but not NMD impairment, was dampened after multivariable adjustment (FMD unadjusted beta = - 1.36 (SE 0.58), p = 0.02; adjusted beta = - 1.16 (SE 0.78), p = 0.14 and NMD unadjusted beta = - 7.68 (SE 1.78), p < 0.0001; adjusted beta = - 5.33 (SE 2.46), p = 0.03). Within the gout group, there was an inverse correlation between FMD and sUA (R = - 0.5, p = 0.003), and between FMD and hsCRP (R = - 0.42, p = 0.017), but not between NMD and sUA or hsCRP. Compared with healthy controls, subjects with gout have reduced arterial function. Individual comorbidities are insufficient to account for differences between gout and control groups, but multiple comorbidities may collectively contribute to impairment in endothelium-dependent arterial responsiveness. Endothelial impairment is also related to sUA and hsCRP, markers of gout severity and inflammation respectively. Studies to determine whether gout therapy may improve arterial responsiveness are warranted.

BACKGROUND:Patients undergoing cardiovascular (CV) procedures often have suboptimal CV risk factor control and may benefit from strategies targeting healthy lifestyle behaviors and education. Implementation of prevention strategies may be particularly effective at this point of heightened motivation. METHODS:A prospective, randomized, pilot study was conducted in 400 patients undergoing a nonurgent CV procedure (cardiac catheterization ± revascularization) to evaluate the impact of different prevention strategies. Patients were randomized in a 1:1:1 fashion to usual care (UC; group A, n = 134), in-hospital CV prevention consult (PC; group B, n = 130), or PC plus behavioral intervention program (telephone-based motivational interviewing and optional tailored text messages) (group C, n = 133). The primary end point was the Δ change in non-high-density lipoprotein cholesterol (non-HDL-C) from baseline to 6 month. RESULTS:The mean age was 64.6 ± 10.8 years, 23.7% were female, and 31.5% were nonwhite. After 6 months, the absolute difference in non-HDL-C for all participants was -19.8 mg/dL (95% CI -24.1 to -15.6, P < .001). There were no between-group differences in the primary end point for the combined PC groups (B and C) versus UC, with a Δ adjusted between group difference of -5.5 mg/dL (95% CI -13.1 to 2.1, P = .16). Patients in the PC groups were more likely to be on high-intensity statins at 6 months (52.9% vs 38.1%, P = .01). After excluding participants with baseline non-HDL-C <100 mg/dL (initial exclusion criterion), Δ non-HDL-C and Δ low-density lipoprotein cholesterol were improved in the PC groups compared to UC (non-HDL-C -8.13 mg/dL [-16.00 to -0.27], P = .04; low-density lipoprotein cholesterol -7.87mg/dL [-15.10 to -0.64], P = .03). CONCLUSIONS:Although non-HDL-C reduction at 6 months following a nonurgent CV procedure was not significant in the overall cohort, an increased uptake in high-potency statins may translate into improved long-term health outcomes and cost reductions.